Submissions for variant NM_000314.8(PTEN):c.956_959del (p.Thr319fs)

dbSNP: rs398123330

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078630	SCV000110486	pathogenic	not provided	2013-03-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491886	SCV000580026	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-26	criteria provided, single submitter	clinical testing	The c.956_959delCTTT pathogenic mutation, located in coding exon 8 of the PTEN gene, results from a deletion of 4 nucleotides at positions 956 to 959, causing a translational frameshift with a predicted alternate stop codon (p.T319Kfs*24). This mutation has been reported in a patient meeting relaxed International Cowden Consortium operational criteria for Cowden Syndrome at age 40 (Tan et al. Am J Hum Genet. 2011 Jan 7;88(1):42-56). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801647	SCV000941434	pathogenic	PTEN hamartoma tumor syndrome	2020-08-02	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the PTEN gene (p.Thr319Lysfs*24). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 85 amino acids of the PTEN protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Cowden or Cowden-like syndrome (PMID: 21194675). ClinVar contains an entry for this variant (Variation ID: 92836). This variant disrupts the C-terminus of the PTEN protein. Other variant(s) that disrupt this region (p.Ala333Serfs*10) have been determined to be pathogenic (PMID: 10468583, 10698513, 24905788, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000078630	SCV002756744	pathogenic	not provided	2022-05-12	criteria provided, single submitter	clinical testing	Reported in an individual with personal history suspicious for PTEN Hamartoma Tumor syndrome (Tan et al., 2007); Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24905788, 24307375, 21194675, 31062505, 10698513, 10468583)
Myriad Genetics, Inc.	RCV003453008	SCV004189611	pathogenic	Cowden syndrome 1	2023-10-02	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.